Poly(ester urea) adhesion barriers for use in the treatment of hernia-mesh repair

Abstract

In various embodiments, the present invention is directed to a degradable poly(ester urea) (PEU)-based adhesion barrier, particularly suitable for use in connection with surgical mesh repair in the treatment of hernias and other soft tissue injuries comprising an amino acid based poly(ester urea) backbone and one or more zwitterionic side chains connected to the amino acid based poly(ester urea) backbone through a sulfide bond. In some other embodiments, the present invention is directed to method of making the PEU-based adhesion barriers comprising: preparing an amino acid based PEU polymer or terpolymer having one or more allyl functional groups; preparing a thiol functionalized zwitterionic compound; and reacting the allyl functionalized PEU polymer or terpolymer with the thiol functionalized zwitterionic compound to form a degradable PEU-based adhesion barrier having an amino acid based PEU backbone having zwitterionic side chains.

What is claimed is: 
     
       1. A poly(ester urea) (PEU) terpolymer for use as an adhesion barrier comprising the reaction product of one or more first amine protected amino acid-based diester monomers, one or more second amine protected amino acid-based diester monomers, one or more amine protected L-tyrosine-based allyloxy diester monomers, a urea bond forming compound and one or more thiol functionalized zwitterionic compounds. 
     
     
       2. The PEU terpolymer of  claim 1  comprising:
 an amino acid based poly(ester urea) backbone, wherein said amino acid based poly(ester urea) backbone comprises: the residue of said one or more first amine protected amino acid-based diester monomer, the residue of said one or more second amine protected amino acid-based diester monomer, the residue of said one or more amine protected L-tyrosine-based allyloxy diester monomer, and the residue of said urea bond forming compound; and 
 one or more zwitterionic side chains, wherein said one or more zwitterionic side chains comprises the residues of said thiol functionalized zwitterionic compounds and is connected to said amino acid based poly(ester urea) backbone through a sulfide bond. 
 
     
     
       3. A poly(ester urea) (PEU)-based adhesion barrier comprising an amino acid based poly(ester urea) backbone and one or more zwitterionic side chains connected to said amino acid based poly(ester urea) backbone through a sulfide bond. 
     
     
       4. The poly(ester urea) (PEU)-based adhesion barrier of  claim 3  wherein the amino acid based poly(ester urea) backbone comprises one or more amino acid-based diester monomer residues and one or more amino acid-based allyloxy diester monomer residues. 
     
     
       5. The poly(ester urea) (PEU)-based adhesion barrier of  claim 4  wherein each one of said one or more amino acid-based diester monomer residues comprises two valine, phenylalanine, leucine, isoleucine, tyrosine, alanine, methionine, glycine, or cysteine with residues separated by from 2 to 20 carbon atoms. 
     
     
       6. The poly(ester urea) (PEU)-based adhesion barrier of  claim 4  wherein said one or more amino acid-based allyloxy diester monomer residues are residues of an amine protected L-tyrosine-1,3-allyloxy-diester monomer. 
     
     
       7. The poly(ester urea) (PEU)-based adhesion barrier of  claim 4  wherein said amino acid-based allyloxy diester monomer is an amine protected L-tyrosine-1,3-allyloxy-diester monomer. 
     
     
       8. The poly(ester urea) (PEU)-based adhesion barrier of  claim 4  wherein said amino acid-based allyloxy diester monomer residue is the residue of a monomer having a formula selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where R is OCH 2 Ph, H, OCH 2 C≡CH, OCH 2 CH 2 CH 2 N 3 , OCH 2 CH 2 CH 2 CH═CH 2 , OCH 2 Ph, OCOCH 2 CH 2 COCH 3  or OH; and c and d are each an integer from about 1 to about 20. 
       
     
     
       9. The poly(ester urea) (PEU)-based adhesion barrier of  claim 4  comprising from about 0.5 to about 50 mole percent L-tyrosine-based allyloxy diester monomer residues. 
     
     
       10. The poly(ester urea) (PEU)-based adhesion barrier of  claim 4  comprising a zwitterionic terpolymer having a formula selected from: 
       
         
           
           
               
               
           
         
         where R is OCH 2 Ph, H, OCH 2 C≡CH, OCH 2 CH 2 CH 2 N 3 , OCH 2 CH 2 CH 2 CH═CH 2 , OCH 2 Ph, OCOCH 2 CH 2 COCH 3  or OH; R 1  is an alkyl or aryl group comprising a zwitterionic moiety; a is an integer from 1 to 20; b is an integer from 1 to 20; c and d are each an integer from about 1 to about 20; x is a mole fraction from about 0 to about 0.995; y is a mole fraction from about 0 to about 0.995; and z is a mole fraction from about 0.005 to about 0.500. 
       
     
     
       11. The poly(ester urea) (PEU)-based adhesion barrier of  claim 4  comprising a zwitterionic terpolymer having a formula selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where R is OCH 2 Ph, H, OCH 2 C≡CH, OCH 2 CH 2 CH 2 N 3 , OCH 2 CH 2 CH 2 CH═CH 2 , OCH 2 Ph, OCOCH 2 CH 2 COCH 3  or OH; a is an integer from 1 to 20; b is an integer from 1 to 20; c and d are each an integer from about 1 to about 20; x is a mole fraction from about 0 to about 0.995; y is a mole fraction from about 0 to about 0.995; and z is a mole fraction from about 0.005 to about 0.500. 
       
     
     
       12. The poly(ester urea) (PEU)-based adhesion barrier of  claim 3  wherein the amino acid based poly(ester urea) backbone comprises the residues of one or more first amino acid-based diester monomer, one or more second amino acid-based diester monomer, and one or more amino acid-based allyloxy diester monomer; and one or more said zwitterionic side chains are attached to said amino acid based poly(ester urea) backbone through said one or more amino acid-based allyloxy diester monomer residues. 
     
     
       13. The poly(ester urea) (PEU)-based adhesion barrier of  claim 12  wherein said one or more first amino acid-based diester monomer comprises two valine, phenylalanine, leucine, isoleucine, tyrosine, alanine, methionine, glycine, or cysteine with residues separated by from 2 to 20 carbon atoms. 
     
     
       14. The poly(ester urea) (PEU)-based adhesion barrier of  claim 12  wherein said one or more first amino acid-based diester monomers comprise two lysine residues separated by from 2 to 20 carbon atoms. 
     
     
       15. The poly(ester urea) (PEU)-based adhesion barrier of  claim 12  wherein said one or more second amino acid-based diester monomer comprises two lysine, phenylalanine, or valine, phenylalanine, leucine, isoleucine, tyrosine, alanine, methionine, glycine, or cystine with residues separated by from 2 to 20 carbon atoms. 
     
     
       16. The poly(ester urea) (PEU)-based adhesion barrier of  claim 12  wherein said one or more second amino acid-based diester monomers comprise two phenylalanine residues separated by from 2 to 20 carbon atoms. 
     
     
       17. The poly(ester urea) (PEU)-based adhesion barrier of  claim 3  wherein said one or more zwitterionic side chains comprise the residue of a zwitterionic thiol. 
     
     
       18. The poly(ester urea) (PEU)-based adhesion barrier of  claim 17  wherein said zwitterionic thiol has the formula: 
       
         
           
           
               
               
           
         
         where R comprises a quaternary ammonium compound and a ring opened sultone; and m, n, and o are each an integer from 1 to 20. 
       
     
     
       19. The poly(ester urea) (PEU)-based adhesion barrier of  claim 17  wherein said zwitterionic thiol has the formula: 
       
         
           
           
               
               
           
         
       
     
     
       20. The poly(ester urea) (PEU)-based adhesion barrier of  claim 3  wherein said one or more zwitterionic side chains comprise a zwitterionic moiety selected from the group consisting of a quaternary ammonium compound, a ring opened sultone, and a combination thereof. 
     
     
       21. The poly(ester urea) (PEU)-based adhesion barrier of  claim 3  having a relative stiffness of from about 20 N/cm to about 40 N/cm as measured by burst force testing. 
     
     
       22. The poly(ester urea) (PEU)-based adhesion barrier of  claim 3  comprising a zwitterionic copolymer having the formula: 
       
         
           
           
               
               
           
         
         where R is OCH 2 Ph, H, OCH 2 C≡CH, OCH 2 CH 2 CH 2 N 3 , OCH 2 CH 2 CH 2 CH═CH 2 , OCH 2 Ph, OCOCH 2 CH 2 COCH 3  or OH; R 1  is an alkyl or aryl group comprising a zwitterionic moiety; R 2  is an amino acid side chain; b is an integer from 1 to 20; c and d are each an integer from about 1 to about 20; y is a mole fraction from about 0.500 to about 0.995; and z is a mole fraction from about 0.005 to about 0.500. 
       
     
     
       23. The poly(ester urea) (PEU)-based adhesion barrier of  claim 3  comprising a zwitterionic terpolymer having the formula: 
       
         
           
           
               
               
           
         
         where R is OCH 2 Ph, H, OCH 2 C≡CH, OCH 2 CH 2 CH 2 N 3 , OCH 2 CH 2 CH 2 CH═CH 2 , OCH 2 Ph, OCOCH 2 CH 2 COCH 3  or OH; R 1  is an alkyl or aryl group comprising a zwitterionic moiety; R 2  is a first amino acid side chain; R 3  is a second amino acid side chain; a is an integer from 1 to 20; b is an integer from 1 to 20; each c and d are each an integer from about 1 to about 20; x is a mole fraction from about 0 to about 0.995; y is a mole fraction from about 0 to about 0.995; and z is a mole fraction from about 0.005 to about 0.500. 
       
     
     
       24. A method of making the poly(ester urea) (PEU)-based adhesion barrier of  claim 3  comprising:
 A) preparing an amino acid based PEU polymer having one or more allyl functional groups; 
 B) preparing a thiol functionalized zwitterionic compound; 
 C) reacting said allyl functionalized PEU terpolymer with said thiol functionalized zwitterionic compound to form a PEU-based adhesion barrier comprising an amino acid based PEU backbone having zwitterionic side chains. 
 
     
     
       25. The method of  claim 24  wherein the step of preparing an amino acid based PEU polymer having an allyl functional group (step A) comprises:
 a) preparing one or more amine protected amino acid-based diester monomers; 
 b) preparing an amine protected allyl functionalized amino acid-based polyester monomer; and 
 c) dissolving said one or more amine protected amino acid-based diester monomers and said amine protected allyl functionalized amino acid-based polyester monomer is a suitable solvent with a suitable water soluble organic base; 
 d) adding a urea bond forming compound to the solution of step c to form an amino acid based PEU polymer having one or more allyl functional groups. 
 
     
     
       26. The method of  claim 25  wherein said amine protected allyl functionalized amino acid-based polyester monomer has a formula selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         where R is OCH 2 Ph, H, OCH 2 C≡CH, OCH 2 CH 2 CH 2 N 3 , OCH 2 CH 2 CH 2 CH═CH 2 , OCH 2 Ph, OCOCH 2 CH 2 COCH 3  or OH; and c and d are each an integer from about 1 to about 20. 
       
     
     
       27. The method of  claim 25  wherein said suitable water soluble organic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and combinations thereof. 
     
     
       28. The method of  claim 24  wherein the step of preparing an amino acid based PEU polymer having an allyl functional group (step A) comprises:
 i) preparing a first amine protected amino acid-based diester monomer; 
 ii) preparing a second amine protected amino acid-based diester monomer; 
 iii) preparing an amine protected allyl functionalized amino acid-based diester monomer; and 
 iv) dissolving said first amine protected amino acid-based diester monomer, said second amine protected amino acid-based diester monomer; and said amine protected allyl functionalized amino acid-based diester monomer is a suitable solvent with a suitable water soluble organic base; 
 v) adding a urea bond forming compound to the solution of step (iv) to form an amino acid based PEU terpolymer having one or more allyl functional groups. 
 
     
     
       29. The method of  claim 28  wherein said first amine protected amino acid-based diester monomers comprises two lysine, phenylalanine, or valine, phenylalanine, lysine, phenylalanine, leucine, isoleucine, tyrosine, alanine, methionine, glycine, or cysteine residues separated by from 2 to 20 carbon atoms. 
     
     
       30. The method of  claim 28  wherein said first amine protected amino acid-based diester monomers comprises two lysine residues separated by from 2 to about 20 carbon atoms. 
     
     
       31. The method of  claim 28  wherein said second amine protected amino acid-based diester monomers comprise two phenylalanine residues separated by from 2 to about 20 carbon atoms. 
     
     
       32. The method of  claim 24  wherein the step of preparing a thiol functionalized zwitterionic compound (step B) comprises:
 1. Reacting 3,3′-dithiodipropionic acid with thionyl chloride under an inert atmosphere to form a 3,3′-dithiodiproionyl chloride intermediate; 
 2. Dissolving 3-dimethyamino-1-propanol in anhydrous dichloromethane under an inert atmosphere and adding the 3,3′-dithiodipropionyl chloride intermediate of step a, wherein said 3-dimethyamino-1-propanol and said 3,3′-dithiodipropionyl chloride intermediate react to form a bis((3-dimethylamino)propyl) 3,3′-disulfanediyldipropionate intermediate; 
 3. Dissolving 1,3-propane sultone in a suitable solvent; 
 4. Dissolving said bis((3-dimethylamino)propyl) 3,3′-disulfanediyldipropionate intermediate in a suitable solvent and adding it to the solution of step (c) to form a zwitterion disulfide intermediate; 
 5. Cleaving said zwitterion disulfide intermediate using 1,4-dithiothreitol (DTT) to produce two thiol functionalized zwitterionic compounds. 
 
     
     
       33. The method of  claim 24  wherein the step of reacting (step C) comprises reacting said allyl functionalized PEU terpolymer with said thiol functionalized zwitterionic compounds to form the PEU-based adhesion barrier comprising an amino acid based PEU backbone having zwitterionic side chains. 
     
     
       34. The method of  claim 24  wherein the step of reacting (step C) comprises:
 I) combining said allyl functionalized PEU terpolymer and said thiol functionalized zwitterionic compounds and adding a suitable photoinitiator; and 
 II) irradiating the combination of step (I) to form the PEU-based adhesion barrier comprising an amino acid based PEU backbone having zwitterionic side chains.